Tumors of the central nervous system known as gliomas represent a significant health concern and their prognosis is poor due to the lack of effective screening or therapies. The main treatments for glioma are surgery and radiation. Surgical resection of aggressive primary tumors is limited by tumor infiltration into normal brain. Radiation has limited efficacy. Thus, novel chemotherapeutic strategies must be developed to effectively treat these gliomas. Primary brain tumors rarely metastasize to other organs but the most aggressive tumors often disperse widely, and proliferate extensively throughout the central nervous system. How this dispersal and proliferation is regulated is unclear, but is likely to depend critically on interactions between the tumor cell and the environment of the brain. Identification of key regulatory signals that control cellular communication and migration will allow development of novel therapeutics to treat gliomas. Cell adhesion molecules are important regulators of adhesion-dependent signals such as contact inhibition of growth and movement. PTPu is a cell surface receptor protein tyrosine phosphatase (RPTP) that is expressed in glial cells. PTPu is a homophilic cell adhesion molecule that is known to regulate cadherin- dependent adhesion. In preliminary studies, we determined that PTPu protein expression is down-regulated in distinct types of human gliomas. Our hypothesis is that PTPu may directly transduce intracellular signals in response to cell adhesion that control migration of glial cells. Consistent with this hypothesis, initial studies suggest that re-expression of PTPjj in a highly dispersive human glioma cell line inhibits migration in an invasion assay using rat brains. In addition, down-regulation of PTPu expression in a non-invasive glioma cell line now causes these cells to migrate in the brain slice invasion assay. These data implicate PTPu in critical events in glioma migration and form the basis for the proposed study.
The specific aims are: I. Analyze PTPu expression in different types of human primary brain tumors II. Alter PTPu expression and catalytic activity in glioma cells and examine migration and invasion III. Determine the molecular mechanisms by which PTP|j negatively regulates cell migration and invasion in glioma cells
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